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Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia

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Abstract

Purpose

To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient.

Methods

A prospective study was developed in 50 children (1–15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central “Dr. Ignacio Morones Prieto” and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX.

Results

A two-compartment open model was selected to describe concentration–time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model.

Conclusions

The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients’ outcomes.

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References

  1. Hunger SP, Mullighan CG (2015) Acute lymphoblastic leukemia in children. N Engl J Med 373(16):1541–1552. https://doi.org/10.1056/NEJMra1400972

    Article  CAS  PubMed  Google Scholar 

  2. Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, Hesseling P, Shin HY, Stiller CA, contributors I (2017) International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol 18(6):719–731. https://doi.org/10.1016/S1470-2045(17)30186-9

    Article  PubMed  PubMed Central  Google Scholar 

  3. Castro-Rios A, Reyes-Morales H, Pelcastre-Villafuerte BE, Rendon-Macias ME, Fajardo-Gutierrez A (2019) Socioeconomic inequalities in survival of children with acute lymphoblastic leukemia insured by social security in Mexico: a study of the 2007-2009 cohorts. Int J Equity Health 18(1):40. https://doi.org/10.1186/s12939-019-0940-3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Inaba H, Greaves M, Mullighan CG (2013) Acute lymphoblastic leukaemia. Lancet 381(9881):1943–1955. https://doi.org/10.1016/S0140-6736(12)62187-4

    Article  PubMed  Google Scholar 

  5. Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM (2011) Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the children’s oncology group (POG 9404). Blood 118(4):874–883. https://doi.org/10.1182/blood-2010-06-292615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL (2016) Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk b-acute lymphoblastic leukemia: a report from children’s oncology group study AALL0232. J Clin Oncol 34(20):2380–2388. https://doi.org/10.1200/JCO.2015.62.4544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Niemeyer CM, Gelber RD, Tarbell NJ, Donnelly M, Clavell LA, Blattner SR, Donahue K, Cohen HJ, Sallan SE (1991) Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (protocol 81-01 update). Blood 78(10):2514–2519

    Article  CAS  PubMed  Google Scholar 

  8. Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP, George SL, Pui CH (1986) Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314(8):471–477. https://doi.org/10.1056/nejm198602203140803

    Article  CAS  PubMed  Google Scholar 

  9. Evans WE, Relling MV, Boyett JM, Pui CH (1997) Does pharmacokinetic variability influence the efficacy of high-dose methotrexate for the treatment of children with acute lymphoblastic leukemia: what can we learn from small studies? Leuk Res 21(5):435–437

    Article  CAS  PubMed  Google Scholar 

  10. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH (1998) Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338(8):499–505. https://doi.org/10.1056/NEJM199802193380803

    Article  CAS  PubMed  Google Scholar 

  11. Schmiegelow K (2009) Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 146(5):489–503. https://doi.org/10.1111/j.1365-2141.2009.07765.x

    Article  CAS  PubMed  Google Scholar 

  12. Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41(1):36–51

    Article  CAS  PubMed  Google Scholar 

  13. Wall AM, Gajjar A, Link A, Mahmoud H, Pui CH, Relling MV (2000) Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia. Leukemia 14(2):221–225

    Article  CAS  PubMed  Google Scholar 

  14. Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. Oncologist 11(6):694–703. https://doi.org/10.1634/theoncologist.11-6-694

    Article  CAS  PubMed  Google Scholar 

  15. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD (2016) Preventing and managing toxicities of high-dose methotrexate. Oncologist 21(12):1471–1482. https://doi.org/10.1634/theoncologist.2015-0164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suthandiram S, Gan GG, Zain SM, Bee PC, Lian LH, Chang KM, Ong TC, Mohamed Z (2014) Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics 15(11):1479–1494. https://doi.org/10.2217/pgs.14.97

    Article  CAS  PubMed  Google Scholar 

  17. Hashiguchi M, Shimizu M, Hakamata J, Tsuru T, Tanaka T, Suzaki M, Miyawaki K, Chiyoda T, Takeuchi O, Hiratsuka J, Irie S, Maruyama J, Mochizuki M (2016) Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population. J Pharm Health Care Sci 2:35. https://doi.org/10.1186/s40780-016-0069-0

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lima A, Sousa H, Monteiro J, Azevedo R, Medeiros R, Seabra V (2014) Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers. Pharmacogenomics 15(12):1611–1635. https://doi.org/10.2217/pgs.14.116

    Article  CAS  PubMed  Google Scholar 

  19. Liu SG, Gao C, Zhang RD, Zhao XX, Cui L, Li WJ, Chen ZP, Yue ZX, Zhang YY, Wu MY, Wang JX, Li ZG, Zheng HY (2017) Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia. Oncotarget 8(23):37761–37772. https://doi.org/10.18632/oncotarget.17781

    Article  PubMed  PubMed Central  Google Scholar 

  20. Radtke S, Zolk O, Renner B, Paulides M, Zimmermann M, Moricke A, Stanulla M, Schrappe M, Langer T (2013) Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood 121(26):5145–5153. https://doi.org/10.1182/blood-2013-01-480335

    Article  CAS  PubMed  Google Scholar 

  21. Zaruma-Torres F, Lares-Asseff I, Reyes-Espinoza A, Loera-Castaneda V, Chairez-Hernandez I, Sosa-Macias M, Galaviz-Hernandez C, Almanza-Reyes H (2015) Association of ABCB1, ABCC5 and xanthine oxidase genetic polymorphisms with methotrexate adverse reactions in Mexican pediatric patients with ALL. Drug Metab Personal Ther 30(3):195–201. https://doi.org/10.1515/dmpt-2015-0011

    Article  CAS  Google Scholar 

  22. Mei L, Ontiveros EP, Griffiths EA, Thompson JE, Wang ES, Wetzler M (2015) Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy. Blood Rev 29(4):243–249. https://doi.org/10.1016/j.blre.2015.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yanagimachi M, Naruto T, Hara T, Kikuchi M, Hara R, Miyamae T, Imagawa T, Mori M, Kaneko T, Morita S, Goto H, Yokota S (2011) Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis. Br J Clin Pharmacol 71(2):237–243. https://doi.org/10.1111/j.1365-2125.2010.03814.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lindbom L, Pihlgren P, Jonsson EN (2005) PsN-toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 79(3):241–257. https://doi.org/10.1016/j.cmpb.2005.04.005

    Article  PubMed  Google Scholar 

  25. Jonsson EN, Karlsson MO (1999) Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58(1):51–64

    Article  CAS  PubMed  Google Scholar 

  26. Keizer RJ, Karlsson MO, Hooker A (2013) Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT 2:e50. https://doi.org/10.1038/psp.2013.24

    Article  CAS  Google Scholar 

  27. Schwartz GJ, Kwong T, Erway B, Warady B, Sokoll L, Hellerstein S, Dharnidharka V, Furth S, Munoz A (2009) Validation of creatinine assays utilizing HPLC and IDMS traceable standards in sera of children. Pediatric Nephrol 24(1):113–119. https://doi.org/10.1007/s00467-008-0957-0

    Article  Google Scholar 

  28. Mould DR, Upton RN (2013) Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT 2:e38. https://doi.org/10.1038/psp.2013.14

    Article  CAS  Google Scholar 

  29. Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9(4):503–512

    Article  CAS  PubMed  Google Scholar 

  30. Pui CH, Relling MV, Sandlund JT, Downing JR, Campana D, Evans WE (2004) Rationale and design of total therapy study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol 83(Suppl 1):S124–S126. https://doi.org/10.1007/s00277-004-0850-2

    Article  PubMed  Google Scholar 

  31. Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, Garcia MJ (2006) Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet 45(12):1227–1238. https://doi.org/10.2165/00003088-200645120-00007

    Article  CAS  PubMed  Google Scholar 

  32. Nader A, Zahran N, Alshammaa A, Altaweel H, Kassem N, Wilby KJ (2017) Population pharmacokinetics of intravenous methotrexate in patients with hematological malignancies: utilization of routine clinical monitoring parameters. Eur J Drug Metab Pharmacokinet 42(2):221–228. https://doi.org/10.1007/s13318-016-0338-1

    Article  CAS  PubMed  Google Scholar 

  33. Odoul F, Le Guellec C, Lamagnere JP, Breilh D, Saux MC, Paintaud G, Autret-Leca E (1999) Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach. Fundam Clin Pharmacol 13(5):595–604

    Article  CAS  PubMed  Google Scholar 

  34. Hui KH, Chu HM, Fong PS, Cheng WTF, Lam TN (2019) Population pharmacokinetic study and individual dose adjustments of high-dose methotrexate in Chinese pediatric patients with acute lymphoblastic leukemia or osteosarcoma. J Clin Pharmacol 59(4):566–577. https://doi.org/10.1002/jcph.1349

    Article  CAS  PubMed  Google Scholar 

  35. Plard C, Bressolle F, Fakhoury M, Zhang D, Yacouben K, Rieutord A, Jacqz-Aigrain E (2007) A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 60(4):609–620. https://doi.org/10.1007/s00280-006-0394-3

    Article  CAS  PubMed  Google Scholar 

  36. El Desoky ES, Ghazally MH, Singh RP, Abdelhamid ON, Derendorf H (2011) Population pharmacokinetics of methotrexate in Egyptian children with lymphoblastic leukemia. Ther Drug Monit 33(4):548

    Google Scholar 

  37. Kim IW, Yun HY, Choi B, Han N, Park SY, Lee ES, Oh JM (2012) ABCB1 C3435T genetic polymorphism on population pharmacokinetics of methotrexate after hematopoietic stem cell transplantation in Korean patients: a prospective analysis. Clin Ther 34(8):1816–1826. https://doi.org/10.1016/j.clinthera.2012.06.022

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank for the assistance of Marlen Melendez, Mariana Morales and Malena Najera, as well as nurses, medical and technical staff from the Hemato-Oncology Pediatric Service at Hospital Central “Dr Ignacio Morones Prieto” and their contributions to the present study.

Funding

This work was supported by Joint Fund for the Promotion of Scientific and Technological Research (FOMIX) through National Council for Science and Technology and State Government from San Luis Potosí (Register FMSLP-2014-02-250277) and Sectorial Fund of Health Research and Social Security from National Council for Science and Technology (Register 272549).

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Authors and Affiliations

  1. Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava Martínez #6, Zona Universitaria, C.P. 78290, San Luis Potosí, Mexico

    Susanna E. Medellin-Garibay, Nadia Hernández-Villa, Miriam Nayeli Morales-Barragán, Karla Paulina Valero-Rivera, Juan Eduardo Reséndiz-Galván, Rosa del Carmen Milán-Segovia & Silvia Romano-Moreno

  2. Hospital Central “Dr. Ignacio Morones Prieto”, Av. Venustiano Carranza #2395, Zona Universitaria, C.P. 78290, San Luis Potosí, Mexico

    Lourdes Cecilia Correa-González & Juan José Ortiz-Zamudio

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  1. Susanna E. Medellin-Garibay
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  2. Nadia Hernández-Villa
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  3. Lourdes Cecilia Correa-González
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Correspondence to Silvia Romano-Moreno.

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Medellin-Garibay, S.E., Hernández-Villa, N., Correa-González, L.C. et al. Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 85, 21–31 (2020). https://doi.org/10.1007/s00280-019-03977-1

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